CZ296342B6 - Substituted piperazine derivative, process for its preparation, its use when preparing a medicament and pharmaceutical composition in which the derivative is comprised - Google Patents

Abstract

The present invention relates to a substituted piperazine derivative of the general formula I, in which A, B, Xe1, Xe2, Rea, Reb and Q have specific significances, and pharmaceutically acceptable salts thereof. These compounds exhibit antithrombotic and anticoagulant properties due to their inhibition of Factor Xa. The invention further relates to a process for preparing such substituted piperazine derivative, as well as its use in the preparation of a medicament and to a pharmaceutical composition in which said derivative is comprised as active substance.

Description

A substituted piperazine derivative, a process for its preparation, its use in the preparation of a medicament and a pharmaceutical composition comprising the derivative

Technical field

The invention relates to a substituted piperazine derivative, a process for its preparation, its use in the manufacture of a medicament having antithrombotic and anticoagulant activity and a pharmaceutical composition comprising said substituted piperazine derivative as an active ingredient.

BACKGROUND OF THE INVENTION

It is believed that the antithrombotic and anticoagulant effect exerted by the compounds of the invention is due to their potent inhibitory activity against the activated coagulation protease known as factor Xa. Factor Xa is one of a number of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the last protease in the series, and factor Xa is the upstream protease that cleaves prothrombin to form thrombin.

Certain compounds are known to have factor Xa inhibitory activity and are reviewed in R. B. Wallis, Current Opinion in Therapeutic Patents, 1993, 1173-1179. Thus, it is known that two proteins, one as antistatin and the other as anticoagulant protein (TAP), are specific Factor Xa inhibitors that have antithrombotic properties in various animal models of thrombotic disease.

It is also known that certain non-peptide compounds have Factor Xa inhibitory properties. Of the low molecular weight inhibitors reported in R. B. Wallis et al., All had a strongly basic group such as an amidinophenyl group or an amidinonaphthyl group.

We have now found that certain heterocyclic derivatives have factor Xa inhibitory activity. Many of the compounds of the present invention are also preferred as selective factor Xa inhibitors, i.e., the factor Xa enzyme is strongly inhibited at concentrations of the test compound that do not inhibit or inhibit less the thrombin enzyme, which is also a member of a variety of blood coagulation enzymes.

PCT International Patent Application WO 9610022 discloses certain heterocyclic piperazine compounds as Factor Xa inhibitors. PCT International Publication No. WO 97 28129, published after the priority date of this application, also discloses certain heterocyclic piperazine compounds as Factor Xa inhibitors. PCT International Publication No. WO 9730971, published after the priority date of this application, discloses benzamidine-type compounds as factor Xa inhibitors.

SUMMARY OF THE INVENTION

The compounds of the present invention are active in the treatment or prevention of various disorders where anticoagulant treatment is required, for example in the treatment or prevention of thrombotic conditions such as coronary artery disease and cerebral vascular disease. Other examples of such diseases include various cardiovascular diseases such as myocardial infarction, atherosclerotic plaque formation, vein or artery thrombosis, coagulation syndromes, vein damage including angioplasty reocclusion and restenosis, and coronary artery bypass surgery, blood clotting vascular surgical techniques or operations such as hip replacement, insertion of artificial heart valves or in the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, ischemia and angina (including unstable angina).

-1 CZ 296342 B6

The compounds of the invention are useful as inhibitors of blood coagulation in ex vivo situations, such as the storage of blood or other biological samples suspected of containing factor Xa and in which coagulation is detrimental.

The present invention provides a substituted piperazine derivative of the Formula I

0) in which

A 5- or 6-membered monocyclic aromatic ring group having 1, 2 or 3 ring nitrogen atoms optionally substituted by one, two or three substituents selected from halogen, oxo, carboxy, trifluoromethyl, cyano, amino, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkyl or C 1 -C 4 dialkylamino contains 1 to 4 carbon atoms;

B is a phenylene ring group optionally substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, and alkynyl containing 2 to 4 carbon atoms, the substituent - (CH ₂ ) _n Y 'in which n is 0 to 4 and Y ¹ is selected from hydroxy, amino, (C 1 -C 4) alkoxy, (C 2 -C 4) alkenyloxy atoms, alkynyloxy of 2 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino 1,1-dioxothiomorpholino groups nu, piperazin-1-yl, 4-alkylpiperazin-1-yl in which the alkyl radical contains 1 to 4 carbon atoms, the alkylthio group containing 1 to 4 carbon atoms, the alkylsulfinyl group containing 1 to 4 carbon atoms, the alkyl sulfonyl group containing 1 to 4 carbon atoms 1 to 4 carbon atoms, alkanoylamino having 2 to 4 carbon atoms, benzamido, alkylsulfonamido of 1 to 4 carbon atoms and phenylsulfonamido, the substituent - (CH 2) n Y ² wherein n is 0-4 and Y ² is selected from the group consisting of carboxy , carbamoyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N-alkylcarbamoyl in which the alkyl radical contains 1 to 4 carbon atoms, až, atom-dialkylcarbamoyl in which each alkyl radical contains 1 to 4 carbon atoms carbon atoms, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl a thiomorpholinocarbonyl group, a 1-oxothiomorpholinocarbonyl group, a 1,1-dioxothiomorpholinocarbonyl group, a piperazin-1-ylcarbonyl group, a 4-alkylpiperazin-1-ylcarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms, an alkylsulfonamidocarbonyl group, the radical contains from 1 to 4 carbon atoms, phenylsulfonamidocarbonyl and benzenesulfonamidocarbonyl, the substituent -X ³ -L ² -Y ² in which X ³ is CON (R ⁵ ), CON (L ² -Y ² ), C (R ⁵⁾ ) 2O, O, N (R ⁵⁾ or N (L ² -Y ^2), L ² represents an alkylene group having 1 to 4 carbon atoms, Y ² has the meanings given above and each ^R independently represents hydrogen or alkyl 1-4 carbon atoms, and -X ³ -L ³ Y ', wherein X ³ is CON (R ⁵ ), CON (R ⁵ ) Y ¹ ), C (R ⁵ ) ₂ O, O, N (R ⁵ ) or N (L ³ -Y '), L ³ represents an alkylene group having 2 to 4 carbon atoms, Y ¹ has a The meanings given above and each R ⁵ independently represent a hydrogen atom or an alkyl group

C 1 -C 4 carbon atoms, wherein each heterocyclic group in the B substituent optionally carries 1 or 2 substituents selected from the group consisting of carboxy, carbamoyl, C 1 -C 4 alkyl, alkoxycarbonyl, wherein the alkoxy moiety it contains 1 to 4 carbon atoms, an N-alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms and a Ν, dial-dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, and each phenyl group in a substituent group B optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, (C 1 -C 4) alkyl, (C 2 -C 4) alkenyl, (C 2 -C 4) alkynyl, (C 1 -C 4) alkynyl up to 4 carbon atoms, alkenes (C 2 -C 4) -alkoxy and (C 2 -C 4) alkynyloxy group;

R ^a and R ^b independently represent hydrogen, hydroxy, oxo, carboxy and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms or each independently represent one of the groups - (CII2) n, - (CIfyjn -NRR ^1, -CO -R, -CO-NRR ¹ , - (CH 2) _n -CO-R and - (CH ₂ ) _n -CO "NRR ¹ , in which n is 0, 1 or 2 and R and R ^{1 are} independently hydrogen, (C 1 -C 4) alkyl, (C 2 -C 4) alkenyl, (C 4 -C 4) alkynyl, (C 1 -C 4) hydroxyalkyl, (C 1 -C 4) -alkyl group; an alkoxycarbonylalkyl group in which the alkoxy radical and the alkyl radical having 1 to 4 carbon atoms, or R and R ¹ together may form a 5 or 6-membered, optionally substituted, saturated or partially unsaturated heterocyclic ring which may be in addition to the nitrogen atom to which R and R ¹ are attached, contain 1 or 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,

X ¹ is SO ₂ , CH ₂ or CO,

X ² is SO ₂ , CH ₂ or CO, and

Q is phenyl, naphthyl, phenylalkyl in which the alkyl moiety contains 1 to 4 carbon atoms, phenylalkenyl in which the alkenyl moiety contains 2 to 4 carbon atoms, phenylalkynyl in which the alkynyl moiety contains 2 to 4 carbon atoms, or a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and Q is optionally substituted with one, two or three substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro , trifluoromethylsulfonyl, carboxy, carbamoyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, alkenyloxy C 2 -C 4 alkynyloxy, C 2 -C 4 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino. atoms, a dialkylamino group in which each alkyl radical contains 1 to 4 carbon atoms, an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms, an N-alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms, Ν, Ν- a dialkylcarbamoyl group in which the alkyl group contains 1 to 4 carbon atoms, an alkanoyl group containing 2 to 4 carbon atoms, an alkanoylamino group containing 2 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group in which an alkoxy radical and an alkyl radical contain 1 to 4 carbon atoms, a carboxyalkyl group in which the alkyl radical contains 1 to 4 carbon atoms, an alkoxycarbonylalkyl group in which the alkoxy radical and the alkyl radical contain 1 to 4 carbon atoms, a carbamoylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms, N- an alkylcarbamoylalkyl group in which each alkyl radical contains 1 to 4 carbon atoms, N, N-dialkyl

-C6-296342 B6 carbamoylalkyl in which each alkyl radical contains 1 to 4 carbon atoms, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, heteroaryloxy, heteroarylthio, heteroarylthio, heteroarylthio, heteroarylthio, heteroarylthio wherein said heteroaryl substituent or heteroaryl group in the heteroaryl-containing substituent is a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and said phenyl substituent, heteroaryl substituent, phenoxy a substituent, a phenylthio substituent, a phenylsulfone substituent, a heteroaryloxy substituent, a heteroarylthiosubstitute, a heteroarylsulfinyl substituent, a heteroarylsulfonyl substituent, a benzyl substituent, or a benzoyl substituent. optionally bears 1, 2 or 3 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino containing 1-4 carbon atoms, a dialkylamino group in which each alkyl radical contains 1 to 4 carbon atoms, an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms, an N-alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms, A Ν, Ν-dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms and an alkanoylamino group containing 2 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.

Preferred is a substituted piperazine derivative of the formula I as defined above, wherein A is a pyridyl, pyrimidinyl or pyridazinyl ring group, more preferably a 4-pyrimidinyl or 4-pyridyl group.

Preferred is a substituted piperazine derivative of the formula I as defined above in which B is para-phenyl.

Preferred is a substituted piperazine derivative of the formula I as defined above, wherein R ^a and R ^{b are} both hydrogen.

Preferred is a substituted piperazine derivative of the formula I as defined above, wherein X ¹ is CO.

Preferred is a substituted piperazine derivative of the formula I as defined above, wherein X ² is SO ₂ .

Preferred is a substituted piperazine derivative of the formula I as defined above, wherein A is a pyridyl, pyrimidinyl or pyridazinyl group, B is a para-phenylene group, X ² is SO ₂ and Q is a styryl or naphthyl group optionally substituted with a fluorine atom, an atom chloro or bromo, or a phenyl group, optionally substituted with a fluorophenyl, chlorophenyl or bromophenyl group, and pharmaceutically acceptable salts thereof.

Preferred is a substituted piperazine derivative of formula (I) as defined above which is selected from 1- (6-bromonaphth-2-ylsulfonyl) -4- [4- (4-pyrimidinyl) benzoyl] piperazine and 1- (6-bromonaphthyl). 2-ylsulfonyl) -4- [4- (4-pyridazinyl) benzoyl] piperazine, and pharmaceutically acceptable salts thereof.

-4GB Z9634.4 B6

The present invention also provides a pharmaceutical composition comprising a substituted piperazine derivative of formula (I) as defined above and a pharmaceutically acceptable diluent or pharmaceutically acceptable carrier.

The invention also provides the use of a substituted piperazine derivative of the formula I as defined above in the preparation of a medicament for use in inhibiting factor Xa.

Finally, the present invention provides a process for the preparation of a substituted piperazine derivative of the formula I as defined above, comprising:

(a) for the preparation of a substituted piperazine derivative of the formula I in which X ¹ is CO, the reaction of an amine of the formula II

HN

N-X-Q

R ^w in which X ² , R ^a , R ^b and Q are as defined above, with an acid of the general formula ΙΠ

A-B-COOH;

(U1) wherein A and B have the above meanings,

b) for the preparation of a substituted piperazine derivative of the formula I in which X ¹ is CH _{2 by} reductive amination of the keto compound of the formula VI

A-B-COH (VI) wherein A and B are as defined above, with an amine of the above formula Π;

c) reacting a compound of formula VII

wherein B, X ¹ , X ² and Q have the above meanings and Z represents a halogen atom with an activated metallized or borane derivative of Ring A;

d) reacting a compound of formula VIII

A-B — X — N

NH (VIII) in which A, B, X ¹ , R ^a and R ^b are as defined above, with a compound of formula IX (IX) wherein X ² and Q are as defined above and Z is halogen;

-5GB 296342 B6

e) reacting a compound of the above formula II with a compound of the formula X to prepare a substituted piperazine derivative of the formula I wherein X ¹ is SO ₂

AB-SO ₂ -Z (X) wherein A and B have the above meanings and Z represents a halogen atom or a sulfonyloxy group;

f) reacting a compound of formula XX to prepare a substituted piperazine derivative of formula I wherein X ² is CO

(XX) wherein A, B, X ¹ , R ^a and R ^b are as defined above, with an acid of formula QCOOH, wherein Q is as defined above;

g) for the preparation of a substituted piperazine derivative of the formula I in which X ² is CH ₂ , reacting a compound of the formula XX as defined above with a ketone of the formula QCOH in which Q is as defined above; and

h) for the preparation of a substituted piperazine derivative of the Formula I wherein X ¹ is SO 2 in which B carries a C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, 1-oxothiomorpholino or 1,1 -dioxothiomorfolinoskupinu wherein X ² represents a group SO2, wherein Q bears alkylsulfinyl group having 1 to 4 carbon atoms, alkylsulphonyl containing 1 to 4 carbon atoms, phenylsulfinyl, phenylsulfonyl, heteroarylsulfinyl or heteroarylsulfonyl group, oxidising a corresponding compound of formula I, wherein X ¹ is thio.

A preferred substituted piperazine derivative of the invention is a substituted piperazine derivative of the above formula (I) wherein:

A represents a 5- or 6-membered monocyclic aromatic ring group containing 1, 2 or 3 ring nitrogen atoms optionally substituted by one, two or three substituents selected from the group consisting of halogen, trifluoromethyl, cyano, amino, hydroxy, nitro, alkyl (C 1 -C 4) group, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, or dialkylamino group, in which each alkyl radical contains one to four carbon atoms;

B represents a phenylene ring group optionally substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, and alkynyl containing 2 to 4 carbon atoms, the substituent - (CH 2 Y ¹ in which n is 0 to 4 and Y ¹ is selected from the group consisting of hydroxy, amino, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, alkynyloxy (C 2 -C 4) -alkyl, (C 1 -C 4) -alkylamino, dialkylamino in which each alkyl radical contains 1 to 4 carbon atoms, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino

-6C.L · ZZ / OJ ^ Z. 1,1-dioxothiomorpholino, piperazin-1-yl, 4-alkylpiperazin-1-yl in which the alkyl radical contains 1 to 4 carbon atoms, the alkylthio radical having 1 to 4 carbon atoms, the alkylsulphinyl radical 1 to 4 carbon atoms, C 1 -C 4 alkylsulfonyl, C 2 -C 5 alkanoylamino, benzamido, C 1 -C 4 alkylsulfonamido and phenylsulfonamido, - (CH ₂ ) _n Y ² in which n is 0 to 4 and Y ² is selected from the group consisting of carboxy, carbamoyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N-alkylcarbamoyl in which the alkyl radical contains 1 to 4 carbon atoms, Ν, dial-dialkylcarbamoyl, wherein each alkyl radical contains from 1 to 4 carbon atoms, pyrrolidin-1-ylcarbonyl, piperidine okarbonylovou group, morpholinocarbonyl, thiomorpholinocarbonyl, 1-oxothiomorfolinokarbonylovou, 1,1-dioxothiomorfolinokarbonylovou group alkylsulfonamidokarbonylovou group in which the alkyl portion contains 1 to 4 carbon atoms, and a group fenylsulfonamidokarbonylovou benzensulfonamidokarbonylovou 15 group, -X ³ -L ² - Y ² wherein X ³ is CON (R ⁵ ), CON (L ² -Y ² ),

C (R ⁵ ) 2 O, O, N (R ⁵ ) or N (L ² -Y ² ), L ² represents an alkylene group having 1 to 4 carbon atoms, Y ² has the meanings given above and each R ⁵ independently represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, and R ³ -L ³ -X Y ', wherein X ³ is a group -CON (R ^5), CON (L ^{3 -Y),} C ^(R5) 2O, O , N (R ⁵ ) or N (L ³ -Y '), L ³ represents an alkylene group containing 2 to 4 carbon atoms, Y ¹ has the meanings given above, and each R ⁵ independently represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms; carbon atoms or a substituent selected from the group consisting of piperazin-1-ylcarbonylalkyl in which the alkyl moiety contains 1 to 4 carbon atoms and 4-alkylpiperazin-1-ylcarbonylalkyl in which each alkyl moiety contains 1 to 4 carbon atoms, wherein each heterocyclic group in the substituent of group B optionally carries 1 or 2 substituents selected from a plurality of substituents carboxy, carbamoyl, C1-C4 alkyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N-alkylcarbamoyl in which the alkyl radical contains 1 to 4 carbon atoms and Ν, Ν-dialkylcarbamoyl a group in which each alkyl radical contains from 1 to 4 to 30 carbon atoms, and each phenyl group in substituent group B optionally carries 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, (C 1 -C 4) alkyl atoms, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy and C 2 -C 4 alkynyloxy;

X ¹ has the meanings specified in claim 1;

R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxy, oxo, 40 carboxy and alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms and one of the following groups:

- (CH ₂ ) -R ^a , in which n represents 0 and R ^a represents an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a carboxyalkyl group, wherein the alkyl radical contains 1 to 4 carbon atoms or an alkoxycarbonylalkyl group in which the alkoxy radical and the alkyl radical contain 1 to 4 carbon atoms;

- (CH 2 CO-NRR ¹ in which n 'is 0, 1 or 2 and R ¹ and R ¹ are hydrogen or C 1 -C 4 alkyl or R ¹ and R ¹ together form 50 1-pyrrolidinyl, 1-piperidino , 1-piperazinyl or 4-morpholino;

X ² and Q are as defined in claim 1;

and pharmaceutically acceptable salts thereof.

-7EN 296342 B6

If pharmaceutically acceptable salts of the compounds of formula (I) are required, these salts may be prepared, for example, by reacting said compound with a suitable acid or base in a conventional manner.

If an optically active form of the compounds of formula (I) is desired, this form can be obtained, for example, by carrying out the above procedures using optically active starting materials or by resolution of the racemic form of said compounds using conventional procedures, for example by diastereoisomeric salt formation using chromatographic techniques. using chiral-specific enzymatic methods or by adding an auxiliary special chiral compound to aid separation.

As mentioned above, the compounds of formula I are inhibitors of the Factor Xa enzyme. The effects of such inhibition can be demonstrated using one or more of the standard assays described below:

a) Measurement of factor Xa inhibition

In an in vitro assay system based on the method of Kettner et al., J. Biol. Chem., 1990, 265, 18289-18297, various concentrations of the test compound are dissolved in a buffer at pH 7.5 containing 0.5% polyethylene glycol (PEG 6000) and incubated at 37 ° C with human factor Xa (0.001 units / ml). , 0.3 mL) 15 minutes. Add chromogenic substrate S-2765 (kabi Vitrum AB, 20 μΜ) and incubate for 20 minutes at 37 ° C and measure the absorbance at 405 nm. The maximum reaction rate is determined and compared to a control containing no test compound. The inhibitor potency is expressed as an IC ₅₀ value.

b) Measurement of thrombin inhibition

Repeat procedure (a) except that human thrombin (0.005 units / ml) and chromoegene substrate S-2238 (Kabi Vitrum AB, 7μΜ) are used.

c) Measurement of anticoagulant activity

An in vitro test in which the venous blood of a human, rabbit or rat is collected and added directly to the sodium citrate solution (3.2 g / 100 ml, 9 parts blood per 1 part citrate solution). Centrifugation (1000 g, 15 minutes) is prepared for blood plasma and stored at 2-4 ° C. A conventional prothrombin time test (PT) is performed in the presence of different concentrations of test compound and the concentration of test compound required for twice the clotting time, CT2, is determined. In the PT assay, test compound and blood plasma are incubated at 37 ° C for 10 minutes. Tissue of thromboplasin with calcium (Sigma Limited, Poole, England) is added and fibrin formation and clot formation time are measured.

d) In vivo activity test for multiple intravenous clotting in rats

Starved female Alderley Park rats (300-450 g) were pre-administered orally (5 ml / kg) of compound or carrier (5% DMSO / PEG 200) at various times prior to Intraval® anesthesia (120 mg / kg i.p.). The left carotid artery and right carotid artery are exposed and cannulated. A 1 ml blood sample is taken from the carotid artery and transferred to a 3.2% trisodium citrate solution. 0.5 ml of whole blood is then treated with EDTA and used to determine platelet count and the residue centrifuged (5 minutes, 2000 g) and the resulting plasma is frozen for subsequent determination of drug, fibrinogen or thrombin antithrombin complex (TAT) levels. Recombinant human tissue factor (Dade Innovin Cat. B421250), diluted according to manufacturer's specifications, is infused (2 ml / kg / hour) into the vessel for 60 minutes. Immediately after the end of the infusion, a 2 ml blood sample is taken and, as above, the platelet count, drug level, plasma fibrinogen concentration and TAT complex are determined. Platelet counting is performed using a T540 blood analyzer. Fibrinogen plasma levels and TAT levels were determined using a clotting assay (Sigma Cat. 880-B) and a TAT ELISA (Boehring). The plasma concentration of the compound is bioassays using human factor Xa and chromogenic substrate S2765 (Kabi), extrapolated from the standard curve (Fragmin) and expressed

-8CL · BO in anti-factor Xa units. Data are analyzed as follows: tissue factor-induced platelet counts are normalized to platelet counts prior to dosing and drug activity is expressed as percent inhibition of tissue factor-induced thrombocytopenia compared to vehicle-treated animals. Compounds are active when there is a statistically significant (p <0.05) inhibition of TF-induced thrombocytopenia.

e) Ex vivo test of anticoagulant activity

The test compound is administered intravenously or orally to a group of Alderley Park Wistar rats. Thereafter, the animals are anesthetized at various times, blood is drawn and a PT coagulation assay is performed analogously to the above.

f) In vivo measurement of antithrombotic activity

The formation of a precipitate is induced using an analogous procedure to that described by Vogel et al., Thromb. Research, 1989, 54, 399-410. A group of Alderley Park Wistar rats sleep and the hollow vein is surgically exposed. The side vessels are sutured and the two loose ends of the thread are placed 0.7 cm around the lower hollow vein. The test compound is administered intravenously or orally. At appropriate times, tissue thromboplastin (30 μΐ / kg) is then administered through the cervical vessel after 10 seconds, the two threads are closed, thereby causing blood to accumulate in the ligated portion of the hollow vein. After 10 minutes, the ligated tissue is excised and the precipitate is collected, dried and weighed.

In general, the compounds of formula I have activity at the following concentrations or doses in at least one of the above tests a) to c):

test a): IC ₅₀ (factor Xa) in the range, for example, 0.001 to 25 μΜ;

test b): IC ₅₀ (thrombin), for example, more than 40 μΜ;

test c): CT2 (PT) in the range, for example, 0.1 to 50 μΜ.

The present invention includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

In another embodiment, the present invention provides pharmaceutical compositions comprising a heterocyclic derivative of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

The compositions may be in a form suitable for oral use, for example in the form of tablets, capsules, aqueous or oily solutions, suspensions or emulsions; for topical use, for example in the form of a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example, in the form of nasal spray or nasal drops; for vaginal or rectal use, for example in the form of suppositories; for administration by inhalation, for example as a well-spread powder such as dry powders, microcrystalline form or liquid aerosol; for sublingual or buccal use, for example in the form of tablets or capsules; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion use), for example in the form of a sterile aqueous or oily solution or suspension. In general, the above compositions may be prepared in conventional manner using conventional additives.

The amount of active ingredient (i.e., the heterocyclic derivative of Formula I, or a pharmaceutically acceptable salt thereof), which combination with one or more ingredients to produce a single dosage form will, of course, vary depending upon the subject being treated and the mode of administration. For example, a composition intended for oral administration to a human will usually contain, for example, 0.5 mg to 2 g of the active ingredient in combination with a suitable amount of the additive which may vary from 5 to 98% by weight of the total composition. A unit dosage form will usually contain about 1 mg to 500 mg of the active ingredient.

-9EN 296342 B6

In another embodiment, the present invention also provides a heterocyclic derivative of Formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

The invention also encompasses the use of such an active ingredient in the manufacture of a medicament for use in:

(i) inducing an inhibitory effect against factor Xa; (ii) inducing an anticoagulant effect;

(iii) inducing an antithrombotic effect;

(iv) treating factor Xa mediated diseases or conditions;

(v) treating diseases or conditions mediated by thrombosis;

(vi) treating coagulation disorders; and / or (vii) treating thrombosis or embolism due to factor Xa-mediated coagulation.

The invention also encompasses a method of inducing the effects described above, or treating the diseases or disorders as defined above), comprising administering to a warm-blooded animal in need thereof an effective amount of the active ingredient as defined above.

The dosage level of a compound of Formula I for therapeutic or prophylactic purposes will vary according to the nature and severity of the condition being treated, the age and sex of the animal or patient, and the route of administration, according to principles known in medicine. As mentioned above, the compounds of Formula I are useful for treating or preventing various disorders in which anticoagulant therapy is indicated. When using a compound of Formula I for this purpose, it will generally be administered with a daily dose in the range, for example, 0.5 to 100 µg / kg body weight / day, and will be administered in divided doses. Generally, lower doses will be administered with the parenteral route of administration, for example intravenous administration, for example, 0.01 to 10 mg / kg body weight / day. For preferred and highly preferred compounds of the invention, generally lower doses, e.g.

Although the compounds of Formula I are primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including humans, they may also be used, if appropriate, to achieve an anticoagulant effect, for example during ex vivo storage of whole blood or developing biological tests for the compounds. that have anticoagulant effects.

The compounds of the present invention may be administered alone or may be administered together with other pharmacologically active agents such as thrombolytic agents, for example tissue plasminogen activator or derivatives thereof or straptokinases. The compounds of the present invention may also be administered, for example, with known platelet aggregation inhibitors (e.g., aspirin, thromboxane antagonists or thromboxane synthase inhibitors), known hypolipidemic agents, or known anti-high pressure agents.

The invention will be further illustrated by the following examples, in which, unless otherwise indicated:

(i) the evaporation is carried out on a rotary evaporator under vacuum and the treatment is carried out after removal of the solid residue by filtration;

(ii) the operations are carried out at room temperature, that is, in the range of 18-25 ° C in an atmosphere of an inert gas such as argon.

(Iii) column chromatography (ultra fast progress) and medium pressure liquid chromatography (MPLC) are usually performed on silica gel gauge Kieselgel (# 9385) or on reverse phase silica gel Gauge Lichroprep RP-18 (# 9303) from E Gauges, Darmstadt, Germany; alternatively, high pressure liquid chromatography (HPLC) is performed on a Dynamax C-18 60 A reverse phase preparative column;

(iv) yields are given for illustration only and are not necessarily the highest achievable yields;

(v) the target products of Formula I have satisfactory elemental analysis and their structure has been confirmed by nuclear magnetic resonance (NMR) and mass spectral techniques; unless otherwise stated, perdeuterodimethylsulfoxide solutions were used to determine NMR spectral data of the end products of Formula I, chemical shift values were measured on a delta scale; the following abbreviations are used: s is a singlet, d is a doublet, t is a triplet, kv is a quartet, m is a multiplet;

(vi) intermediates are not usually fully characterized and purity was verified by thin layer chromatography, infrared spectroscopy, or NMR analysis;

(vii) The melting point was determined using a Mettler SP62 automatic melting point apparatus or an oil bath apparatus; the melting points of the end products of formula (I) are usually determined after crystallization from conventional organic solvents such as ethanol, methanol, acetone, ether or hexane, alone or in a mixture; and (viii) the following abbreviations are used:

DMF N, N-dimethylformamide;

EtOAc ethyl acetate;

DMSO dimethylsulfoxide.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Methyl 4- (4-pynmidinyl) benzoate (0.41 g, 1.9 mmol) was stirred at room temperature in ethanol (20 mL) and 2N aqueous sodium hydroxide solution (20 mL) for 1 h. The resulting suspension was evaporated in vacuo and azeotroped in toluene, thionyl chloride (100 mL) and dimethylformamide (1 drop) were added and the reaction mixture was heated to boiling for 1 hour. with dichloromethane to give 4- (4-pyrimidinyl) benzoyl chloride The acid chloride is suspended in dichloromethane (100 mL) and 1- (6-bromonaphth-2-ylsulfonyl) piperazine hydrochloride (0.545 g, 1) is added as a solid in two portions. The reaction mixture was stirred at room temperature overnight, then evaporated in vacuo, and the resulting solid was partitioned between ethyl acetate (100 mL) and water (2 x 100 mL). The organic layer was dried over sulfate magnesium, filtered and evaporated in vacuo to give a black oil which was purified by chromatography (silica gel: 40%, 50%, 60% ethyl acetate / hexane) to give 1- (6-bromonaphth-2-ylsulfonyl) -4- [4]. - (4-pyrimidinyl) benzoyl] piperazine as a white solid;

1 H NMR (250 MHz, CDCl 3) δ = 2.94 and 3.18 ppm (m, 4H), δ = 3.40 and

3.83 ppm (m, 4H), δ = 7.49 ppm (d, 2H), δ = 7.83 ppm (m, 2H), δ = 8.10 ppm (dd, 1H), δ = 8, 14 to 8.23 ppm (m, 4H), δ = 8.43 ppm (d, 1 H), δ = 8.49 ppm (s, 1 H), δ = 8.89 ppm (d, 1 H), δ = 9.26 ppm (s, 1 H); Mass Spectroscopy (M + H) ⁺ 536.

-11 CZ 296342 B6

Methyl 4- (4-pyrimidinyl) benzoate was prepared as follows:

(a) 4 (3H) -Pyrimidone (7.00 g, 72.8 mmol) was heated to boiling in thionyl chloride (50 mL) and dimethylformamide (3 mL) for 1 hour. No clear solution was obtained, so another portion of thionyl chloride (50 mL) was added and the reaction mixture was heated to reflux for an additional hour. The reaction mixture was evaporated in vacuo. Ether (500 mL) was added and the solid was destroyed. The resulting yellow solid was filtered and washed with ether. A precipitate formed in the filtrate. This was filtered to give 4-chloropyrimidine as a light brown solid (4.79 g);

@ 1 H NMR (250 MHz, CDCl3) .delta. = 6.62 ppm (d, 1H), .delta. = 8.07 ppm (dd, 1H), .delta. = 9.11 ppm (s, 1H); Mass Spectroscopy (M + H) ⁺ 115.

(b) 4-Carboxybenzeneboronic acid (10.22 g, 61.2 mmol) was heated quark in methanol (70 mL) with concentrated sulfuric acid (0.5 mL) overnight. The reaction mixture was allowed to cool to room temperature and then evaporated in vacuo. The resulting oil was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give the corresponding methyl ester as a white solid (9.85 g); @ 1 H NMR (250 MHz, CDCl3) .delta. = 3.85 ppm (s, 3H), .delta. = 7.89 ppm (s, 4H), .delta. = 8.19 ppm (s, 2H); mass spectroscopy (MH) ^- 179.

(c) 1,1'-Bis (diphenylphosphino) ferrocene (2.48 g, 4.5 mmol) and palladium acetate (1.0 g, 4.5 mmol) were stirred at 50 ° C in toluene (25 mL) in nitrogen atmosphere for 30 minutes, then cooled to room temperature. Add boronic acid methyl ester from step b) above (2.2 g, 11.2 mmol), 4-chloropyrimidine hydrochloride from step a) above (1.69 g, 11.2 mmol) and potassium fluoride (3.9 g) , 67 mmol) and then water (25 mL). The reaction mixture was heated to boiling under nitrogen overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a black oil which was purified by chromatography (silica gel; 100% ethyl acetate) to give methyl 4- (4-pyrimidinyl) benzoate as a brown solid (1). 17 g); 1 H NMR (250 MHz, CDCl 3) δ = 3.91 ppm (s, 3H), δ = 8.13 & 8.36 ppm (dd, 4H), δ = 8.19 ppm (dd, 1 Η), δ = 8.94 ppm (d, 1 H), δ = 9.32 ppm (d, 1 H); Mass Spectroscopy (M + H) ⁺ 215.

Example 2

Methyl 4- (4-pyrimidinyl) benzoate (0.72 g, 3.4 mmol) was stirred at room temperature in ethanol (100 mL) and 2N aqueous sodium hydroxide solution (20 mL) for 1 h. A 2N aqueous hydrochloric acid solution was then added until a precipitate formed. The resulting suspension was evaporated in vacuo and azeotroped with toluene. Thionyl chloride (100 mL) and dimethylformamide (1 drop) were added and the reaction mixture was heated to boiling for 1 hour. The reaction mixture was evaporated in vacuo and azeotroped with toluene to give 4- (4-pyrimidinyl) benzoate. The acid chloride was suspended in dichloromethane (100 mL), and 4- (6-chloro-2-ylsulfonyl) -2-methoxycarbonylpiperazine hydrochloride (1.0 g, 2.7 mmol) was added as a solid, followed by triethylamine (3, 1, 2). 8 mL, 27 mmol). The reaction mixture was stirred overnight and evaporated in vacuo. The resulting solid was partitioned between ethyl acetate (200 mL) and water (2x200 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo to give a brown solid which was purified by chromatography (silica gel; 100% ethyl acetate) to give 1- (6-chloro-2-ylsulfonyl) -3-methoxycarbonyl-4. - [4- (4-pyrimidinyl) benzoyl] piperazine as a white solid. This was purified again by chromatography (silica gel: 30%, 40%, 60%, 65% ethyl acetate / hexane) to give a white crystalline solid (1.051 g); 1 H NMR (250 MHz, CDCl 3) δ = 2.75 ppm (m, 1H), δ = 2.92-4.64 ppm & 5.35 ppm (m, 9H), δ = 7.52 ppm (d, 2H), δ = 7.73 ppm (dd, 1 Η), δ = 7.80 ppm (dd, 1 Η), δ = 8.10 ppm (d, 1 Η), δ = 8.14 to 8, 31 ppm (m, 5H), δ = 8.51 ppm (d, 1 Η), δ 8.89 ppm (d, 1H), δ = 8.89 ppm (d, 1H), δ = 9.26 ppm (s, 1 H); Mass Spectroscopy (M + H) ⁺ 551.

-12GB 296342 B6

Example 3

4- (4-Pyridyl) benzoic acid (238 mg, 1.2 mmol) was suspended in dimethylformamide (5 mL) with triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then cooled to 5 ° C. Carbonyldiimidazole (194 mg, 1.2 mmol) was added and the reaction was allowed to warm slowly to room temperature over 1 hour. 4- (6-Bromo-naphth-2-ylsulfonyl) -piperazine hydrochloride (470 mg, 1.2 mmol) was added in one portion as a solid, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate (50 mL) and washed twice with saturated aqueous sodium bicarbonate solution (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by chromatography (silica gel; 2%, 4%, 6%, 8%, 10% methanol / ethyl acetate) to give 1- (6-bromonaphth-2-ylsulfonyl) -4- [4- (4- pyridyl) benzoyl] piperazine as a white solid (90 mg); 1 H NMR (CDCl 3) δ = 3.07 ppm (s, 4H), δ = 3.59 ppm (s, 4H), δ = 7.27 & 7.46 ppm (dd, 4H), δ = 7, 18 & 8.64 ppm (dd, 4H), δ = 7.34 ppm (m, 2H), δ = 8.17 ppm (dd, 2H), δ = 8.39 ppm (d, 1H), δ = 8.47 ppm (s, 1H); Mass Spectroscopy (M + H) ⁺ 536.

4- (4-Pyridyl) benzoic acid was prepared as follows:

a) 4-Cyanophenylboronic acid (1.49 g, 10 mmol), 4-bromopyridine hydrochloride (1.97 g, 10 mmol), 10% palladium on carbon (322 mg) and anhydrous sodium carbonate (2.15 g, 20 mmol) mmol) were heated to boiling in a mixture of ethanol (12 mL) and water (3 mL), overnight under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, then evaporated in vacuo. The resulting white solid was partitioned between ethyl acetate (3x100 mL) and water (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by chromatography (silica gel; 50%, 60%, 70%, 80% ethyl acetate / iso-hexane) to give 4- (4-pyridyl) benzonitrile as a crystalline white solid (1.60 g), @ 1 H NMR (CDCl3) .delta. = 7.77 ppm (dd, 2H), .delta. = 7.99 ppm (m, 4H), .delta. = 8.69 ppm (dd, 2H); Mass Spectroscopy (M + H) ⁺ 181.

b) 4- (4-Pyridyl) benzonitrile (0.5 g, 2.8 mmol) was dissolved in concentrated sulfuric acid (10 mL) and heated at 110 ° C overnight. The reaction mixture was allowed to cool to room temperature and then poured into ice-water. Sodium hydroxide beads are added until a precipitate forms. Then, they were filtered to give 4- (4-pyridyl) benzamide as a white solid (0.40 g). 1 H NMR (CDCl 3) δ = 7.77 ppm (d, 2H) δ = 7.89 ppm (d, 2H) δ = 8.02 ppm (d, 2H), δ = 8.65 ppm (3s, 2H), mass spectroscopy (M + H) ⁺ 199.

c) 4- (4-Pyridyl) benzamide (0.35 g, 1.8 mmol) was suspended in ethanol (5 mL). A 10% (w / w) aqueous sodium hydroxide solution was added and the reaction mixture was heated to boiling for two hours and then allowed to cool to room temperature. The reaction mixture was acidified to pH 7 with concentrated sulfuric acid. The precipitated white precipitate was filtered off to give 4- (4-pyridyl) benzoic acid (238 mg).

Example 4

4- (2-Pyridyl) benzoic acid (199 mg, 1 mmol) was suspended in dimethylformamide (5 mL) and triethylamine (0.14 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes and then cooled to 5 ° C. Carbonyldiimidazole (162 mg, 1 mmol) was added and the reaction was allowed to warm slowly to room temperature over 1 hour. 1- (6-Bromo-naphth-2-ylsulfonyl) -piperazine hydrochloride (393 mg, 1 mmol) was added as a solid in one portion and the reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. The crude product was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting white solid was purified by chromatography (silica gel; 100% ethyl acetate) to give 1- (6-bromonaphth-2-ylsulfonyl) -4- [4- (2-pyridyl) benzoyl] piperazine as a white solid (92 mg); 1 H NMR (CDCl 3) δ = 3.09 ppm (s, 4H), δ = 3.62 ppm (s, 4H), δ = 7.37 ppm (t, 1H), δ = 7.51 to 7, 99 ppm (m, 4H), δ = 7.42 and 8.08 ppm (dd, 4H), δ = 8.17 ppm (dd, 2H), δ = 8.40 ppm (d, 1 Η), δ ~ 8.47 ppm (s, 1H), δ = 8.66 ppm (dd, 1H); mass spectroscopy (M + H + 536.

Example 5 1- (6-Chlomaphth-2-ylsulfonyl) -4- (4-iodobenzoyl) piperazine (920 mg, 1.7 mmol), diethyl 3-pyridylborane (250 mg, 1.7 mmol), tetrabutylammonium bromide (110 mg, 0.34 mmol), tetrakis (triphenylphosphine) palladium (69 mg, 0.06 mmol) and potassium hydroxide (286 mg, 5.1 mmol) were heated to boiling in dry tetrahydrofuran (100 mL) for two hours under a nitrogen atmosphere. . The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The resulting solid was purified by flash chromatography (silica gel; 100% dichloromethane, 50% ethyl acetate / hexane, 100% ethyl acetate) to give an oil. Dissolve the oil in ethyl acetate (100 mL) and wash with saturated aqueous sodium bicarbonate (100 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo to give a white foam that was triturated with hexane. The solid is purified by chromatography (silica gel; 40%, 50%, 60%, 70% ethyl acetate / hexane) to give 1- (6-chloro-2-sulfonyl) -4- [4- (3-pyridyl) benzoyl]. ] piperazine as a white solid (322.4 mg); @ 1 H NMR (CDCl3) .delta. = 3.1 ppm (s, 4H), .delta. = 3.6 ppm (s, 4H), .delta. = 7.46 ppm (d, 2H), .delta. 67 ppm (m, 1 H), δ = 7.70 to 7.79 ppm (m, 3 H), δ = 7.83 ppm (dd, 1 H), δ = 8.09 ppm (dt, 1 Η), δ = 8.15 ppm to 8.31 ppm (m, 3 Η), δ = 8.50 ppm (s, 1 Η), δ 8.60 ppm (dd, 1 Η), δ = 8.90 ppm (d (1H); Mass Spectroscopy (M + H) ⁺ 492.

1- (6-Chlomaphth-2-ylsulfonyl) -4- (4-iodobenzoyl) piperazine was prepared as follows:

1- (6-Chloro-2-ylsulfonyl) piperazine (0.65 g, 2.1 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.9 mL, 21 mmol) was added at room temperature. 4-Iodobenzoyl chloride (0.56 g, 2.1 mmol) was added in one portion as a solid and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo and then partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (100 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting white solid was purified by chromatography (silica gel; 50% ethyl acetate / hexane) to give 1- (6-chloro-2-ylsulfonyl) -4- (4-iodobenzoyl) piperazine as a white solid (0.97 g); 1 H NMR (Perdeuterodimethylsulfoxide) δ = 3.05 ppm (s, 4H), δ = 3.53 ppm (s, 4H), δ = 7.11 ppm & 7.74 ppm (dd, 4H), δ = 7 65-7.84 ppm (m, 2H), δ = 8.10 ppm to 8.28 ppm (m, 3H), δ = 8.47 ppm (s, 1H); Mass Spectroscopy (M + H) ⁺ 540.

Example 6

4- (2-Methyl-4- (3-pyridyl) benzoyl) piperazine (0.41 g, 1.5 mmol) was dissolved in dichloromethane (50 mL) at room temperature. 6-Chlomaphthalenesulfonyl chloride (0.38 g, 1.5 mmol) and triethylamine (1 mL, 7.5 mmol) were added and the reaction was stirred overnight. The reaction mixture was evaporated in vacuo. The crude product was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by chromatography (silica gel; 50%, 60% ethyl acetate / hexane) to give 1- (6-chloromaphit-2-ylsulfonyl) -4- [2-methyl-4- (3-pyridyl) benzoyl] piperazine as white solids (508.4 mg); @ 1 H NMR (CDCl3) .delta. = 2.15 ppm (s, 3H), .delta. = 2.94-3.25 ppm (m, 6H), .delta. = 3.78 ppm (m, 2H), .delta. 23 ppm (d, 1H), δ = 7.44 to 7.62 ppm (m, 3H), δ 7.70 ppm (dd, 1H),

-14EN 296342 B6 δ = 7.84 ppm (dd, 1 Η), δ = 8.08 ppm (m, 1H), pyridyl 5-H), δ = 8.12 to 8.28 ppm (m, 3H) ), δ = 8.48 ppm (s, 1 H), δ = 8.59 ppm (dd, 1 H), δ = 8.88 ppm (d, 1 H); Mass Spectroscopy (M + H) ⁺ 506.

4- (2-Methyl-4- (3-pyridyl) benzoyl) piperazine was prepared as follows:

a) Suspend 4-Bromo-2-methylbenzoic acid (11.55 g, 53.7 mmol) in thionyl chloride (40 mL). One drop of dimethylformamide was added and the resulting mixture was stirred at 69 ° C until gas evolution ceased. The reaction mixture was evaporated in vacuo and azeotroped twice with toluene. The resulting oil was dissolved in dichloromethane (100 mL) and cooled to 5 ° C. Tert-Butyl-1-piperazine carboxylate (10.0 g, 53.7 mmol) was added portionwise over 1 hour followed by triethylamine (37.5 mL, 260 mmol). The reaction mixture was stirred overnight at room temperature and then evaporated in vacuo. The crude product was dissolved in ethyl acetate (750 mL) and washed with 2N aqueous sodium hydroxide solution and then brine. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a brown oil. The product was crystallized from ethyl acetate / hexane to give beige crystals (9.01 g); @ 1 H NMR (CDCl3) .delta. = 1.40 ppm (s, 9H), .delta. = 2.20 ppm (s, 3H), .delta. = 3.10 ppm (m, 2H), .delta. = 3.26 ppm (m) Δ = 3.41 ppm (m, 2H), δ = 3.62 ppm (s, 2H), δ = 7.15 ppm (d, 1H), δ = 7.44 ppm (dd, 1) H), .delta. = 7.52 ppm (d, 1H); Mass Spectroscopy (M + H) ⁺ 383.

b) The product of step a) above (3.83 g, 10 mmol), diethyl 3-pyridylborane (1.47 g, 10 mmol), tetrabutylammonium bromide (0.65 g, 2 mmol), tetrakis (triphenylphosphine) palladium ( 0.40 g, 0.35 mmol) and potassium hydroxide (1.68 g, 30 mmol) were heated under vacuum in dry tetrahydrofuran (75 mL) for two hours under nitrogen. The reaction mixture was allowed to cool to room temperature and then partitioned between ethyl acetate (250 L) and water (2 x 500 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil was purified by flash chromatography (silica gel; 100% ethyl acetate) to give t-butyl 4- [2-methyl-4- (3-pyridyl) benzoyl] piperazine carboxylate as a brown solid (1.78 g); @ 1 H-NMR (CDCl3) .delta. = 1.41 ppm (s, 9H), .delta. = 2.60 ppm (s, 3H), .delta. = 3.17 ppm (m, 2H), .delta. = 3.27 ppm (m, 2H), δ = 3.44 ppm (m, 2H), δ 3.66 ppm (s, 2H), δ = 7.61 ppm (d, 1H), δ = 7.49 ppm (dd, 1H) Δ = 7.59 ppm (dd, 1 H), δ = 7.61 ppm (s, 1 H), δ = 8.08 ppm (m, 1 H), δ = 8.5 8 ppm (dd, 1H) .delta. = 8.90 ppm (d, 1H); Mass Spectroscopy (M + H) ⁺ 382.

c) The product of step b) above (1.66 g, 4.35 mmol) was dissolved in dichloromethane (50 mL) at room temperature. Trifluoroacetic acid (10 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo, then partitioned between ethyl acetate and 2N aqueous sodium hydroxide solution. The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo to give 4- [2-methyl-4- (3-pyridyl) benzoyl] piperazine as a colorless oil (410 g).

Example 7

A solution of 4- (4-pyridyl) benzoic acid (398 mg), hydroxybenzotriazole (338 mg) and dicyclohexylcarbodiimide (453 mg) was stirred at room temperature for 1 hour, then 1- (6-chloro-2-ylsulfonyl) was added. Piperazine (621 mg) and stirring was continued at room temperature for an additional 16 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo to give a foam which is partially purified by flash chromatography (20.7 kPa on silica gel (ART 9585 gauge)) eluting with 2.5% methanol in dichloromethane with 0.1% SG 0.88 ammonia solution. A white foam (473 mg) was obtained. A portion of this foam (110 mg) was purified by preparative on a Dynamax® C-18 60A column eluting with 0.1% trifluoroacetic acid in aqueous acetonitrile at a gradient of 30% to 70% acetonitrile. The solution was freeze dried to give a white foam. There was thus obtained 1- (6-chloro-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine as trifluoroacetate (83.5 mg); mp 175-176 ° C; H HNMR (250 ppm, perdeuterodimethylsulfoxide at

- 15GB 296342 B6

100 ° C) δ = 3.17 (t, 4H), 3.47 (t, 4H), 7.47 (d, 2H), 7.62-7.86 (m, 6H), 8.08- 8.48 (m, 3H), 8.43 (s, 1H), 8.66 (d, 2H) ppm; mass spectroscopy: m / z 492/494 (M + H) &lt; + & gt ^; (1 Cl pattern).

Example 8

4- (2-Methyl-4-pyridyl) benzoic acid (62 mg), 1- (6-bromonaphth-2-ylsulfonyl) piperazine (94 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61 mg) ) was dissolved in dimethylformamide (2.5 mL) and the resulting solution was stirred at room temperature for 16 hours. Excess dimethylformamide was evaporated in vacuo, water was added and the resulting precipitate was filtered off, washed well with cold water and dried over phosphorus pentoxide. The solid thus obtained is purified by flash chromatography (20.7 kPa) on silica gel (Meter ART 9385), eluting with 2.5% methanol / dichloromethane. There was thus obtained 1- (6-bromonaphth-2-ylsulfonyl) -4- [4- (2-methyl-4-pyridyl) benzoyl] piperazine (99 mg); mp 204-205 ° C; 1 H NMR (300 Hz, perdeuterodimethylsulfoxide) δ = 2.48 (s, 3H), 3.03 (s, 4H), 3.57 (broad s, 4H), 7.46 (t, 3H), 7, 56 (s, 1H), 7.77 (d, 2H), 7.83 (d, 2H), 8.17 (q, 2H), 8.42 (s, 1H), 8.48 (d, 2H) ppm; mass spectroscopy: m / z 550/552 (M + H) &lt; + & gt ^; (1 Br model).

4- (2-Methyl-4-pyridyl) benzoic acid was prepared as follows:

(a) Iso-Amylnitrite (7.9 g) was slowly added to a solution of ethyl 4-aminobenzoate (4.95 g) in 2-picoline (100 mL) at room temperature. The resulting mixture was heated at 100 ° C for 2 hours and then the excess picoline was evaporated in vacuo to give a black oil. The mixture of isomers thus obtained is purified by flash chromatography at 20.7 kPa on silica gel (gauge ART 9385) eluting with 25% (v / v) ethyl acetate in isohexane. There was thus obtained ethyl 4- (2-methyl-4-pyridyl) benzoate (0.2 g) as a brown gum which was sufficiently pure for the next reaction: @ 1 H NMR (300 MHz, DMSO) .delta. = 1.32 (t, 3H), 2.53 (s, 3H), 4.33 (qu, 2H), 7.52 (d, 1H), 7.61 (s, 1H), 7.92 (d, 1H); 2H), 8.05 (d, 2H), 8.52 (d, 1H) ppm; mass spectroscopy: m / z 242 (M + H) &lt; + &gt;.

(b) Ethyl 4- (2-methyl-4-pyridyl) benzoate (185 mg) was dissolved in methanol (7.5 mL) and 1.0 M sodium hydroxide solution (3.75 mL) and heated at 60 ° C for 3 hours. Noc: 2 ° C. The volume of the mixture was evaporated in half and then 10 mL of water was added, the solution was neutralized to pH 7.0 with 1.0 M hydrochloric acid, the resulting precipitate was filtered off and dried over phosphorus pentoxide to give 4- (2-methyl-4). -pyridyl) benzoic acid as a light brown solid (73 mg); mp 293-294 ° C; @ 1 H NMR (304 MHz, CDCl3) .delta. = 2.52 (s, 3H), 7.53 (d, 1H), 7.62 (s, 1H), 7.89 (d, 2H), O 4 (d, 2H), 8.52 (d, 1H) ppm; mass spectroscopy: m / z 214 (M + H) &lt; + &gt;.

Example 9

4- (4-Pyridazinyl) benzoic acid (300 mg), 1- (6-bromonaphth-2-ylsulfonyl) piperazine (484 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (317 mg) were dissolved in dimethylformamide (7.5 ml) and the resulting solution was stirred at room temperature for 16 hours. 50 ml of water are added and the resulting precipitate is filtered off, washed with well cold water and dried over phosphorus pentoxide. There was thus obtained 1- (6-bromonaphth-2-ylsulfonyl) -4- [4- (4-pyridazinyl) benzoyl] piperazine (535 mg); mp 128-130 ° C; @ 1 H NMR (300 MHz, CDCl3 at 100 DEG C.) .delta. = 3.12 (s, 4H), 3.57 (s, 4H), 7.48 (d, 2H), 7.80 (m, 2H), 7.89 (d, 2H), 7.94 (m, 1H), 8.14 (d, 2H), 8.39 (s, 1H), 8.46 (s, 1H), 9.26 (d, 1H), 9.58 (s, 1H) ppm; mass spectroscopy: m / z 537/539 (M + H) &lt; + & gt ^; (1 Br model).

4- (4-Pyridazinyl) benzoic acid was prepared as follows:

(A) A solution of sodium nitrile (1.44 g) in water (3.0 mL) was added slowly at 0 ° C to a stirred solution of ethyl 4-aminobenzoate (3.3 g) in 48% fluoroboric (III). acid (9.4 mL). After the addition was complete, the mixture was stirred at 0 ° C for a further 0.5 hours, then filtered and washed with cold fluoroboric acid (5.0 mL), then ethanol and finally diethyl ether. The thus obtained ethyl (4-diazonium tetrafluoroborate) benzoate (4.60 g) was mixed with dry potassium acetate (3.40 g) and 18-crown-6-0.23 g) and then reacted with pyridazine at room temperature ( 25 ml). The mixture quickly turns black and nitrogen is released. After stirring at room temperature for 16 hours, excess pyridazine was evaporated in vacuo and the black residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over magnesium sulfate and evaporated to give a black residue. The mixture of isomers thus obtained is purified by flash chromatography on an ART 9385 silica gel, eluting with ethyl acetate to give ethyl 4- (4-pyridazinyl) benzoate (1.04 g); mp 110-112 ° C; @ 1 H NMR (300 MHz, CDCl3) .delta. = 1.42 (t, 3H), 4.43 (qu, 2H), 7.68 (dxd, 1H), 7.75 (d, 2H), 8.22 ( d, 2H), 9.28 (d, 1H), 9.50 (d, 1H) ppm; mass spectroscopy: m / z 229 (M + H) &lt; + &gt;.

(b) Ethyl 4- (4-pyridazinyl) benzoate (580 mg) was dissolved in methanol (12.5 mL) and 1.0 M sodium hydroxide solution (12.7 mL) and heated at 60 ° C for 4 hours. The resulting mixture was evaporated to half volume, then water (25 mL) was added, the solution was neutralized to pH 7 with 1.0M hydrochloric acid, the resulting precipitate was filtered off and dried over phosphorus pentoxide to give 4- (4-pyridazinyl) benzoic acid. acid as a light brown solid (503 mg); mp > 330 ° C; @ 1 H NMR (300 MHz, CDCl3) .delta. = 8.05 (m, 5H), 9.32 (d, 1H), 9.67 (s, 1H) ppm; MS: m / z 201 (M + H) &lt; + &gt;.

Example 10

6-Bromo-naphth-2-ylsulfonyl chloride (470 mg) was added in one portion at room temperature to a mixture of 1- [2-methoxycarbonyl-4- (4-pyridyl) benzoyl] piperazine (500 mg) and triethylamine (311 mg) in dichloromethane (5). ml). After 10 minutes, the mixture is evaporated in vacuo and the residue thus obtained is purified by flash chromatography at 20.7 kPa on silica gel (ART 9385 gauge), eluting first with dichloromethane, then with 1% and 2% by volume methanol in dichloromethane. There was thus obtained 1- (6-bromonaphth-2-ylsulfonyl) -4- [2-methoxycarbonyl-4- (4-pyridyl) benzoyl] piperazine (866 mg) as a foam; @ 1 H NMR (250 MHz, CDCl3) .delta. = 3.03 (t, 2H), 3.27 (t, 2H), 3.34 (t, 2H), 3.56 (s, 3H), 3.94 (broad s, 2H), 7.32 (d, 1H), 7.48 (dxd, 2H), 7.70-7.82 (m, 3H), 7.86 (d, 1H), 7 92 (d, 1H), 8.13 (d, 1H), 8.24 (d, 1H), 8.32 (s, 1H), 8.71 (dxd, 2H) ppm; mass spectroscopy: m / z 594/596 (M + H) &lt; + & gt ^; (1 Br model).

1- [2-Methoxycarbonyl-4- (4-pyridyl) benzoyl] piperazine was prepared as follows:

Br

- 17GB 296342 B6

A solution of t-butyloxycarbonylpiperazine (14.4 g) in chloroform (20 ml) was added dropwise at room temperature to a solution of 4-bromophthalic anhydride (17.5 g) in chloroform (50 ml). The reaction mixture was stirred at 60 ° C for 1 hour, then evaporated in vacuo to give an oil. A mixture of isomers (31.9 g) was obtained (structure "C" and "D").

To a solution of the isomeric mixture of C + D acids in acetone (60 mL) was added potassium carbonate (10.7 g) and dimethyl sulfate (9.71 g), and the mixture was stirred at room temperature for 2 hours. The solution containing the E + F esters is filtered and the filtrate evaporated in vacuo to give a gum (33.0g) which is purified by preparative HPLC using PhaseSep NP silica gel, 15-35µm, 60A eluting with 25-50% v / v. ethyl acetate of vizohexane. There was thus obtained structure E (12.86 g), which is a slower isomer;

mp 131-132 ° C; 1 H NMR (400 MHz, CDCl 3) δ = 1.46 (s, 9H), 3.14 (t, 2H), 3.36 (broad s, 2H), 3.56 (broad s, 2H), 3, 77 (broad s, 2H), 3.89 (s, 3H), 7.16 (d, 1H), 7.71 (dxd, 1H), 8.17 (d, 1H) ppm: mass spectroscopy : m / z 427/429 (M + H) &lt; + & gt ^; (1 Br model).

A solution of structure E (4.27 g) in dimethylformamide (40 ml) was deoxigenized by bubbling argon for 5 minutes, then tetrakistriphenylphosphine palladium (1.15 g), bistriphenylphosphine palladium dichloride (0.70 g) and silver oxide (2.32 g) were added. ) and the mixture was stirred at 100 ° C for 5 minutes, then trimethyl- (4-pyridyl) -stannane (3.63 g) was added and the mixture was heated at 100 ° C for a further 15 minutes. room for 20 hours, then filtered through diatomaceous earth 20 and evaporated in vacuo to give a black residue, which was stirred with 1.0 M potassium fluoride (20 mL) for 1 hour and then extracted with ethyl acetate (3x25 mL). , filtered and evaporated to give a black oil which is partially purified by flash chromatography at 20.7 kPa on silica gel (ART 9385 gauge) eluting with 25% and 50% by volume ethyl acetate in isohexane, then 2% and 4% by volume methanol in dichloromethane.

Final purification was performed by MPLC BIOTAGE® P45 eluting with ethyl acetate at 70 kPa to give 1-tert-butoxycarbonyl-4- [2-methoxycarbonyl-4- (4-pyridyl) benzoyl] piperazine (1.94 g);

mp 144-146 ° C; ¹ HNMR (300 MHz, CDCl 3) δ = 1.46 (s, 9H), 3.20 (t, 2H), 3.39 (m, 2H), 3.60 (m, 2H), 3.81 (m, 2H) m, 2H), 3.93 (s, 3H), 7.42 (d, 1H), 7.52 (d, 2H), 7.84 (dxd, 1H), 8.3 (d, 1H) 8.73 (d, 2H) ppm; mass spectroscopy: m / z 37020 (M + H) &lt; + &gt;.

A 2.2 molar solution of hydrogen chloride in diethyl ether (2.9 ml) was added to a solution of structure B (1.05 g) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 4 hours. The supernatant liquors were combined and the remaining gum was triturated with ether to give a white solid, which was treated with a saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate 35 (3 x 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give 1- [2-methoxycarbonyl-4- (4-pyridyl) benzoyl] piperazine (500 mg) as a white foam; @ 1 H NMR (250 MHz, CDCl3) .delta. = 2.45 (m, 2H), 2.62 (m, 2H), 2.90 (m, 2H), 3.39 (m, 2H), 3.68 (s, 3H), 7.33 (d, 1H), 7.62 (dxd, 2H), 7.93 (dxd, 1H), 8.10 (d, 1H), 8.53 (dxd, 2H) ppm; mass spectroscopy: m / z 326 (M + H) &lt; + &gt;.

Example 11

A stirred suspension of 4- (4-pyridyl) benzoic acid (sodium salt) (190 mg, 0.86 mmol) 45 in dichloromethane (10 mL) was treated with oxalyl chloride (0.2 mL, 2.3 mmol) and dimethylformamide ( catalytic amount). After stirring for 2 hours, additional oxalyl chloride (0.2 mL,

2.3 mmol) and dimethylformamide (catalytic amount) and the suspension was stirred for an additional 4 hours. The solvent was evaporated in vacuo and, after drying, suspended in dichloromethane (20 ml) and treated with

2- (hydroxymethyl) -4- (6-bromonaphth-2-ylsulfonyl) piperazine (300 mg, 0.78 mmol) and triethyl 50 amine (0.36 mL, 2.5 mmol). After stirring overnight at room temperature, the mixture was diluted with dichloromethane (20 mL) and water (20 mL). A large precipitate was formed, which was filtered off, dried and recrystallized from ethyl acetate (10 ml) to give 1- (6-bromonaphth-2-ylsulfonyl) -3- (hydroxymethyl) -4- [4- (4-pyridyl) benzoyl] piperazine as colorless solids (250 mg); ¹ H NMR (300 MHz, CDCl 3) δ = 3-4 ppm (broad, 9H), δ = 7.2 ppm (d, 2H),

-18GB 296342 B6 δ = 7.7 ppm (d, 2H), δ = 7.8 ppm (m, 4H), δ = 8.2 ppm (t, 2H), δ 8.4 ppm (s, 1 Η ), δ = 8.45 ppm (s, 1 Η), δ = 8.6 ppm (d, 2H); also signals due to ethyl acetate (1 mol eq) are present; mass spectroscopy: (M + H) ⁺ 566/568 (1Br model); Elemental Analysis: C, 56.8; H, 4.9; N,

6.3%; for C 7 H ₂ 4 Br _{2-NjSO4.C 4 g} H ₂ O requires: C, 56.9; H, 4.9; N, 6.4%.

3- (Hydroxymethyl) -4- (6-bromonaphth-2-ylsulfonyl) piperazine was prepared as follows:

3- (hydroxymethyl) piperazine monoacetate (1.1 g, 6.25 mmol) and triethylamine (2.2 mL, 2.5 eq) were stirred at room temperature in dichloromethane (50 mL) and the suspension was treated with 6- bromonaphth-2-ylsulfonyl chloride (2.0 g, 6.5 mmol). The mixture was stirred overnight and then diluted with additional dichloromethane (50 mL); the solution was then washed with water, saturated sodium bicarbonate solution and brine. After drying (PS paper) and evaporation, a colorless foam (1 g) was obtained. This was chromatographed (silica gel; dichloromethane: methanol 19: 1 by volume) to give 2- (hydroxymethyl) -4- (6-bromonaphth-2-ylsulfonyl) piperazine as a colorless foam (670 mg), which was used without further purification; 1 H NMR (300 MHz, CDCl 3) δ = 2.3 ppm (t, 1H), δ = 2.5 ppm (dt, 1H), δ = 2.9 - 3.1 ppm (m, 3H), δ = 3.5 ppm (dd, 1 H), δ = 3.6 ppm (m, 3 H), δ = 7.6 - 8.0 ppm (m, 4 H), δ ~ 8.1 ppm (s, 1 H) .delta. = 8.3 ppm (s, 1H); mass spectroscopy (M + H) ⁺ 385/387 (1Br, model).

Example 12

A stirred suspension of 4- (4-pyridyl) benzoic acid (133 mg, 0.67 mmol) in dimethylformamide (5 mL) was treated sequentially with i-hydroxybenzotriazole hydrate (108 mg, 0.8 mmol), 1- (3) hydrochloride. dimethylaminopropyl) -3-ethylcarbodiimide (153 mg, 0.8 mmol) and 1- (5-chlorobenzofuran-2-ylsulfonyl) piperazine (201 mg, 0.67 mmol). After stirring overnight, the solvent was evaporated in vacuo and the residue was chromatographed (Meter Art 9385 silica gel, eluting with dichloromethane containing 2% methanol by volume) to give 1- (5-chlorobenzofuran-2ylsulfonyl) -4- [4- (4-pyridyl)] benzoyl] piperazine as a colorless solid (40 mg). @ 1 H NMR (CDCl3) .delta. = 3.2-3.4 ppm (broad s, 4H), .delta. = 3.6-4.0 ppm (broad s, 4H), .delta. = 7.35 ppm (s, 1H) ), δ = 7.5 ppm (m, 6H), δ = 7.7 ppm (m, 3H), δ - 8.7 ppm (d, 2H), mass spectroscopy (M + H) ⁺ 482/484.

1- (5-Chlorobenzofuran-2-ylsulfonyl) piperazine was prepared as follows:

A stirred solution of piperazine (1.15 g, 13.4 mmol) and triethylamine (4.7 mL, 46.5 mmol) in dichloromethane (30 mL) was cooled to ~ 5 ° C, and a solution of 5-chlorobenzofuran- Of 2-sulfonyl chloride (1.69 g, 7.8 mmol) in dichloromethane (10 mL). Stirring is continued for 15 minutes and the reaction mixture is allowed to warm to room temperature with stirring over 2 hours. Water was added to the reaction mixture and the organic layer was separated; This was washed twice with water, once with brine, then dried over magnesium sulfate, filtered and evaporated to give a yellow gum. This was chromatographed (Scale Art 9385 silica gel, eluting with dichloromethane containing increasing amounts of methanol, up to 10% v / v) to give a yellow solid; trituration with diethyl ether gave 5-chlorobenzofuran-2-ylsulfonylpiperazine as a colorless solid (1.11 g) which was used without further purification; ‘H NMR (CDCl 3) δ = 2.8 - 3.0 ppm (t, 4H), δ = 3.2 -

3.4 ppm (t, 4 H), δ = 7.3 ppm (s, 1H), δ = 7.45 ppm (dd, 2H), δ = 7.7 ppm (s, 1H); mass spectroscopy (M + H) &lt; + & gt ^; 301/303.

The necessary starting material 5-chlorobenzofuran-2-ylsulfonyl chloride is prepared as described in European Patent Application 0 355 827 (Mochida, hydantoin derivatives).

Example 13

Further examples are described in Table 1

-19GB 296342 B6

Table

2. O what CN O O .. tf! m kp O φ CN tf! O O in Φ w O tf! φ O »» ·. O w E m ·. Ό Ό cn X h E Ε * ra and í * l OJ *** rri r! 03 / ca · - and Hive tf? (T \ m Γ— < m r ~ 1 ’Φ X rH X <υ X <1) + ¢) N <- < I.E in + at Σ i— < Ό ω in Σ X 0 kO Σ X Q cn O 0 X b in n H fe in r * *** H E ’Ϊ * ID ri E

and • r4 Ό • H

E

-H a

o r — i jz u

• Φ hC jj

1)

E

CN

N

Ό nj i-H

Ή a

>

o λ MU and nj CD

Qt O a s Λ o CQ • 3 a

N <U rH Ό CU

About those> «u Λ Ή

Λ

Prepared according to the method described in Example 1 (c) from 2,6-dimethyl-4-chloropyrimidine and then ester hydrolysis

-X O Φ k0 N * rri X x X m n · at CN r-4 X - xn * ε kD * - * N * CN l> Q n < II CN XD N * it tn ΧΏ CN r * * • r-4 * -x O O <—1 i.e in X xn <N kD with N se X X CN O CN O m WHAT <* 1 x in Ol m

* r - · \ 0 CN r-4 00 00

x x r * C· *** CD O <* ·> r- * r AND. X r ^- * r- Γ- • X X r-4 X X xn CN <N NJ Ξ and in ·. L “l ’Φ o 0 * '(7> n * Γ ' in u> CN LO WHAT O r * C- r — 4

ko n * in - tí * ε p

X 1 * —x F —X CD X Q. X ω X rU £ X • Φ * · (N * x Γ x GT ._. w XJ * - * X _w · »- CN . N * »» T in r- Ό m <N CN * - » rU x 00 • 'ϋ CD CN <* n X O ^ -x. - __ X CD II r- X CN m CN , Ν ’ * E XO O r- AT χ Xjr WHAT x 00 CN <n ** τΓ X <h « N 00 X O β κη r * r-4 ω X w Q X X what r * 1 r-4 CN X 00 * • n N x ε Ώ x 1 * 1 00 Σ O what O O x O N * CD tn <*) - ·. ^with 4 * 3 CN CD

CN \ ϋ ΓΝ x CN CN 00 —X x X X X X <*) Γ * r · and-· x X •O « r-x , —X X Mm X N * CN r4 WHAT x -x ko N * ε Ώ CN X * - ** • M χ-χ * «G what 04 / T CN > x CL. Ch r- xř CN r *. ^ x. X <-4 X X w * H II r4 ® C- " E it X X TJ X « I.E t r> CD r4 Ό Ξ «« « \O X> O CN Cfl CN in O - X X U> n · ·. **** ^ -x Q * * QO X x n r · · - * r4 - _v N x x Ό TJ X * - * «—o X X X X O CN v — í CN CN Γ O x X x About CM ΓΊ ε Ό 4J X » 03 CS

u <u P Ώ O

CQ X 03 O + X U X rM N * LO 1Λ + 5 u X rU r> <D in + ^ 4 X CQ * - * r- < r-4 0 E > at 0 Ό CN * ctf and V4 > CN <υ o O Xi ·· rh n ^ -X 0 C ^ x. α - * 1 -H rH 0 AT r-4 \O rM r-4 > N HIM <u ε X N r-4 >, O C 0 Π5 m □ G fO X r-4 0 C <u r-M T3 • H r4 M 4J r * 4-i • H Λ >, • w N Φ <U υ r-4 N —X 0 M £ and M »» r — 4 with rtj r-4 4J - «4 n 4 * H XJ m O M >. n ·· <1> Ή • r4 and • H 1 0 0) Ό E X! « ^ X. * 4 —X M and kD -H • H 0 > rtí rU 3 r-4 C at - N Ό YEAH and C > 0 X OJ CN and > fO M 1 •• 4 and and and Λ rU and r-4 V4 C * J Π3 Ν ’ rU O 0 AT > O xr Λ! O U-4 v < rN HIM C Ν ’ Qi r-4 03 / r-4 and >. 0 + -H <4 > p IN* > 3 (Q 0 Ό r * Λ at and Λ Her tn N C -H -rM E V4 0 4J •> 4 r-4 • h e 0 Λ 3 «5 at) X \ <o >. Ε Ή >. • 4 Jd rU C She knows and 0 > 1 rt -r4 n and Λ > U4 • * 4 C XJ rh Λ 0 CN O -4 G X rU O -ť4 t 4J 0 »» O X o WHAT N * <0 O <* 5 'IN Him > N 11 N AT Λ XI <3 * - * xz x-r ω rU 0 r-4 _G C HIM rt 4J U O. »» 4J >. 0 >, « υ <« OJ a) rt N Ν ’ N · —1 Ν ’ 0] and and CN XI ^C G Ε ϋ

c • H

-H ÍU

S cl * σ o n ·

O-4 04 m

N

Table 1 (continued)

n ·

ΙΛ

Prepared according to the method described in Example 9 (a) and (b) from methyl 4-amino-2-methoxybenzoate

-21 CZ 296342 B6

Table 1 (continued)

Ό Q r * X + X X CM 'O O 00 cn r · Tr O what O] * <n O X xn cn b. Q * O X O rH <33 - N •O <71 X X X X O O r-f O O cs - «. cn XJ O n 03 /

fú N > 1 0 ru r-t N t 0 J CM N I 0 >. at $ 1 Ol HIM and 'Π1 X and CM 0 t. > CM O > MU 0 '<U> OF) c * O ¹ a C o <e C > u i.e 0 U u • H 0 c • rf 0 u-i E N> u · * £ n ε ε 0 <0 (AT C <0 J m c 0 <4 N C <U X T3 <U C ® r-f 3 4) H TJ C Ě >, Η X g >. τ> Λ X > 'Η Q 0 χ ε - 0 X · Η ·· -d £ -0 k JJ ·· * 3 n M X Ε r-1 \ O JJ -H - And · - * R * 4 >. x - υ ή > - • H φ · * -! Ε Ό 0 Ό C g -rl X 1 N E -O > 4 <O Ή • Η Ο Ν —4 <p · Η • rf Ό • H <- ♦ m -HIM T3 - N χ X u Μ - M Ό 0 ό n • H i 05 / ι Ju ή >. i <0 , Λ >. 0) 1 * 4 U rH m th Ju and r4 U m * -ί and and cn cú >. d> - 44 Oct «(A) ¹ + • H - x Λ _t and • rH 0 3 · a I X and 1 r-f | > • H r— (bJ i * -H rU r — i »» r- <> i • q · and Λ c o a > O r-f X X (U C Ά - * X C r * JJ 0 ΓΒ 4> X (0 <0 r-f JJ Ή flj C Q) X c > 4 '-4> 1 > c>, Ή □ E C 0 Ή « 3 0 -H q X m X .X-C 4J t <ú -η HIM 4-) m O 1 r-f 0 • H> 0 1 rl 0 • Η (*) i r-i r-f • Η l tn r-1 <U HIM > M —s'h CM <U MU X4 o e 3 > N -. 3 ca r-f 3 T3 4 ^ 4 3 r-l *** m WHAT 3 rU and 1> - 3 0> •>. 3 0> < I>. r-f 0 bj Λί CD and a TJ <CD and a O 44 and a and and

L>

Ή

Ή

Ή

• Η

4J 0 0 3 r-f and 0 Λ C υ <s <d Ε > 3 3 O • Η O N C > <OJ -r4 rU r-f r-1 <ú r-4 υ JJ here 01 fu 04 / X Λ! X C E • H 3 OJ HIM 0 ••AT 03 / > 0 O <OJ HIM 0 r-f H N rM >. C <0 r- < 0 Ch O X JJ

Prepared with palladium catalyzed condensation of 2- (N-tert-butoxycarbonylamino) 4-bromopyridine and 4-carboxyethylphenylboronic acid and use of (1,1'-bis (diphenylphosphino) ferrocene) diacetyl palladium

-22GB zyoj42 B6

Table 1 (continued)

O

4)>

xj η TJ o

Ή C

Ό l>

rH

0) 0 and σι o «5 and oj u 4J CQ m

Ό m. — 1 Λί Ή

O c 'íú ra

O

Prepared by reaction of 4- (4-pyrimidinyl) benzoyl chloride with 1- tert -butoxycarbonyl-3-oxopiperazine and then reaction with trifluoroacetic acid

U>

-23EN 296342 B6

Claims (13)

PATENT CLAIMS A substituted piperazine derivative of the Formula I (I) wherein: A 5- or 6-membered monocyclic aromatic ring group containing 1, 2 or 3 ring nitrogen atoms optionally substituted by one, two or three substituents selected from halogen, oxo, carboxy, trifluoromethyl, cyano, amino, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylamino or dialkylamino in each 1 to 4 carbon atoms; B represents a phenylene ring group optionally substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, and alkynyl containing 2 to 4 carbon atoms, the substituent - (CH ₂ ) _n Y 'in which n is 0 to 4 and Y ¹ is selected from hydroxy, amino, (C 1 -C 4) alkoxy, (C 2 -C 4) alkenyloxy atoms, alkynyloxy of 2 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino 1,1-dioxothiomorpholino; a piperazin-1-yl group, a 4-alkylpiperazin-1-yl group having an alkyl radical of 1 to 4 carbon atoms, an alkylthio group of 1 to 4 carbon atoms, an alkylsulfinyl group of 1 to 4 carbon atoms, an alkylsulfonyl group containing 1 to 4 carbon atoms to 4 carbon atoms, alkanoylamino having 2 to 4 carbon atoms, benzamido, alkylsulfonamido of 1 to 4 carbon atoms and phenylsulfonamido, the substituent - (CH 2) n Y ² wherein n is 0-4 and Y ² is selected from the group consisting of carboxy, carbamoyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N-alkylcarbamoyl in which the alkyl radical contains 1 to 4 carbon atoms, Ν, Ν-dialkylcarbamoyl in which each alkyl radical contains 1 to 4 carbon atoms atoms, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl coupon, thiomorpholinocarbonyl, 1-oxothiomorpholinocarbonyl, 1,1-dioxothiomorpholinocarbonyl, piperazin-1-ylcarbonyl, 4-alkylpiperazin-1-ylcarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, alkylsulfonamidocarbonyl, alkylsulfonamidocarbonyl, the radical contains from 1 to 4 carbon atoms, phenylsulfonamidocarbonyl and benzenesulfonamidocarbonyl, the substituent -X ³ -L ² -Y ² in which X ³ is CON (R ⁵ ), CON (L ² -Y ² ), C (R ⁵⁾ 12O, O, N (R ⁵ ) or N (L ² -Y ² ), L ² represents an alkylene group containing 1 to 4 carbon atoms, Y ² has the meanings given above, and each R ⁵ independently represents a hydrogen atom or an alkyl group containing 1-4 carbon atoms, and -X ³ -L ³ Y *, wherein X ³ is CON (R ⁵ ), CON (L ³ -Y '), C (R ⁵ ) ₂ O, O, N ( R ⁵ ) or N (L ³ -Y '); represents an alkylene group having 2 to 4 carbon atoms, Y ¹ has the meanings given above and each R ⁵ independently represents a hydrogen atom or an alkyl group 1-4C, wherein each heterocyclic group in the substituent of group B optionally carries 1 or 2 substituents selected from the group consisting of carboxy, carbamoyl, alkyl of 1 to 4 carbon atoms, alkoxycarbonyl, wherein the alkoxy radical it contains 1 to 4 carbon atoms, an N-alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms and a Ν, Ν-dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, and each phenyl group in the substituent group B optionally bears 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, (C 1 -C 4) alkyl, (C 2 -C 4) alkenyl, (C 2 -C 4) alkynyl, (C 1 -C 4) alkynyl up to 4 carbon atoms, alkene (C 2 -C 4) yloxy and (C 2 -C 4) alkynyloxy group; R ^a and R ^b independently represent a hydrogen atom, a hydroxy group, an oxo group, a carboxy group and an alkoxycarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms or independently represents one of the groups - (CH _{2) n} -R, - (CH _{2) n} -NRR ', -CO-R, -CO-NRR ^1, - (CH _{2) n} -CO-R and - (CH _{2) n} -CO- NRR '; wherein n is 0, 1 or 2 and R and R ^{1 are} independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkynyl up to 4 carbon atoms, a carboxyalkyl group in which the alkyl radical contains 1 to 4 carbon atoms and an alkoxycarbonylalkyl group in which the alkoxy radical and the alkyl radical containing 1 to 4 carbon atoms, or R and R ¹ together may form a 5- or 6-membered group, an optionally substituted, saturated or partially unsaturated heterocyclic ring that may contain, in addition to the nitrogen atom to which R a R ^{1 is} attached, 1 or 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, X ¹ is SO ₂ , CH ₂ or CO, X ² is SO ₂ , CH ₂ or CO, and Q is phenyl, naphthyl, phenylalkyl in which the alkyl moiety contains 1 to 4 carbon atoms, phenylalkenyl in which the alkenyl moiety contains 2 to 4 carbon atoms, phenylalkynyl in which the alkynyl moiety contains 2 to 4 carbon atoms, or a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and Q is optionally substituted with one, two or three substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro , trifluoromethylsulfonyl, carboxy, carbamoyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, alkenyloxy C 2 -C 4 alkyl, C 2 -C 4 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, a dialkylamino group in which each alkyl radical contains 1 to 4 carbon atoms, an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms, an N-alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms, Ν, dial-dialkylcarbamoyl wherein the alkyl moiety contains 1 to 4 carbon atoms, the alkanoyl moiety having 2 to 4 carbon atoms, the alkanoylamino moiety having 2 to 4 carbon atoms, the hydroxyalkyl moiety having 1 to 4 carbon atoms, the alkoxyalkyl moiety in which the alkoxy moiety and the alkyl moiety contain up to 4 ang carboxyalkyl in which the alkyl radical contains 1 to 4 carbon atoms, alkoxycarbonylalkyl in which the alkoxy radical and the alkyl radical contain 1 to 4 carbon atoms, carbamoylalkyl in which the alkyl radical contains 1 to 4 carbon atoms, N- alkylcarbamoylalkyl A group in which each alkyl radical contains from 1 to 4 carbon atoms, an N, N-dialkylcarbamoylalkyl group in which each alkyl radical contains from 1 to 4 carbon atoms, a phenyl group, a heteroaryl group, a phenoxy group, a phenylthio group, a phenylsulfonyl group, phenylsulfonyl, benzyl, benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulfonyl and heteroarylsulfonyl, wherein said heteroaryl substituent or heteroaryl in a heteroaryl-containing substituent is a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from up to 3 heteroatoms a nitrogen atom, an oxygen atom and a sulfur atom, and said phenyl substituent, heteroaryl substituent, phenoxy substituent, phenylthio substituent, phenylsulfone substituent, heteroaryloxy substituent, heteroarylthiosubstitute, heteroarylsulfyl substituent t, the heteroarylsulfonyl substituent, the benzyl substituent or the benzoyl substituent optionally bears 1, 2 or 3 substituents selected from the group consisting of halogen, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, alkyl of 1 to 4 carbon atoms, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, dialkylamino (C 1 -C 4), alkoxycarbonyl (C 1 -C 4) alkoxy, N-alkylcarbamoyl, in which alkyl radical contains 1 to 4 carbon atoms, the Ν, Ν-dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, and the alkanoylamino group containing 2 to 4 carbon atoms, and pharmaceutically acceptable salts thereof. A substituted piperazine derivative of the Formula I according to claim 1, wherein A represents a pyridyl, pyrimidinyl or pyridazinyl ring group. 3. A compound according to claim 2 wherein A is 4-pyrimidinyl or 4-pyridyl. A substituted piperazine derivative of the formula I as claimed in any one of claims 1 to 3 wherein B represents a para-phenylene group. A substituted piperazine derivative of the formula I as claimed in any one of claims 1 to 3, wherein R ^a and R ^{b are} both hydrogen. A substituted piperazine derivative of the formula I according to any one of claims 1 to 3, wherein X ¹ is CO. A substituted piperazine derivative of the formula I according to any one of claims 1 to 3, wherein X ² is SO ₂ . A compound according to claim 1, wherein A is a pyridyl, pyrimidinyl or pyridazinyl group, B is a para-phenylene group, X ² is SO _2, and Q is a styryl or naphthyl group optionally substituted with a fluorine atom, a chlorine atom or a bromine atom, or a phenyl group, optionally substituted with a fluorophenyl, chlorophenyl or bromophenyl group, and pharmaceutically acceptable salts thereof. A substituted piperazine derivative of the formula I according to claim 1, which is selected from the group consisting of 1- (6-Bromo-naphth-2-ylsulfonyl) -4- [4- (4-pyrimidinyl) benzoyl] piperazine and 1- (6-Bromo-naphth-2-ylsulfonyl) -4- [4- (4-pyridazinyl) benzoyl] piperazine, and their pharmaceutically acceptable salts. -26GB 296342 B6 A pharmaceutical composition comprising a heterocyclic derivative of the Formula I as claimed in any one of claims 1 to 9 and a pharmaceutically acceptable diluent or pharmaceutically acceptable carrier. Use of a substituted piperazine derivative according to any one of claims 1 to 9 in the preparation of a medicament for use in inhibiting factor Xa. A process for preparing a substituted piperazine derivative of the Formula I according to claim 1 1, characterized in that it comprises: (a) for the preparation of a substituted piperazine derivative of the formula I wherein X ¹ is CO, reacting an amine of the formula II (II) wherein X ² , R ^a , R ^b and Q are as defined in claim 1 with an acid of the formula ΙΠ A-B-COOH; (ΠΙ) wherein A and B have the meanings specified in claim 1, b) for the preparation of a substituted piperazine derivative of the formula I in which X ¹ is CH _{2 by} reductive amination of the keto compound of the formula VI A-B-COH (VI) wherein A and B are as defined in claim 1, with an amine of formula II above; c) reacting a compound of formula VII R * 7 O <B i X — B — x´ — N N-X-Q R ^b (VII) wherein B, X ¹ , X ² and Q are as defined in claim 1 and Z represents a halogen atom with an activated metallized or borane derivative of Ring A; d) reacting a compound of formula VIII AB - X - (VIII) wherein A, B, X ¹ , R ³ and R ^b have the meanings specified in claim 1, with a compound of formula IX ZX ² -Q (IX) wherein X ² and Q are as defined in claim 1 and Z represents a halogen atom; -27GB 296342 B6 e) for the preparation of a substituted piperazine derivative of the formula I wherein X ¹ is SO ₂ , reacting a compound of the above formula II with a compound of the formula X ab-s ₂ -z (X) wherein A and B have the meanings specified in claim 1 and Z are halogen or sulfonyloxy; f) reacting a compound of formula XX to prepare a substituted piperazine derivative of formula I wherein X ² is CO A-B-X-N NH (XX) wherein A, Β, X ¹ , R ^a and R ^b are as defined in claim 1, with an acid of formula QCOOH, wherein Q is as defined in claim 1; g) for the preparation of a substituted piperazine derivative of formula I wherein X ² is CH ₂ , reacting a compound of formula XX as defined above with a ketone of formula QCOH, wherein Q is as defined in claim 1; and h) for the preparation of a substituted piperazine derivative of the Formula I wherein X ¹ is SO 2 in which B carries a C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, 1-oxothiomorpholino or 1,1 -dioxothiomorfolinoskupinu wherein X ² represents a group SO2, wherein Q bears an alkylsulphinyl radical containing 1 to 4 carbon atoms, alkylsulphonyl containing 1 to 4 carbon atoms, phenylsulfinyl, phenylsulfonyl, heteroarylsulfinyl or heteroarylsulfonyl group, oxidation of a corresponding compound of of formula I wherein X ¹ is thio. A substituted piperazine derivative according to claim 1, wherein: A represents a 5- or 6-membered monocyclic aromatic ring group containing 1, 2 or 3 ring nitrogen atoms optionally substituted by one, two or three substituents selected from the group consisting of halogen, oxo, carboxy, trifluoromethyl, cyano, amino, hydroxy , nitro, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkylamino or dialkylamino (C 1 -C 4) -alkyl; of 1 to 4 carbon atoms; B is a phenylene ring group optionally substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, and alkynyl containing 2 to 4 carbon atoms, the substituent - (C ¹ -C ⁶ ynyl ⁾ wherein n is 0 to 4 and Y ¹ is selected from hydroxy, amino, (C 1 -C 4) alkoxy, (C 2 -C 4) alkenyloxy, (C 2 -C 4) alkynyloxy C 2 -C 4 alkyl, C 1 -C 4 alkylamino, dialkylamino in which each alkyl radical contains 1 to 4 carbon atoms, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1- dioxothiomorpholino groups u, piperazin-1-yl, 4-alkylpiperazin-1-yl in which the alkyl radical contains 1 to 4 carbon atoms, the alkylthio group containing 1 to 4 carbon atoms, the alkylsulfinyl group containing 1 to 4 carbon atoms, the alkylsulfonyl group -28CZ 296342 B6 group containing 1 to 4 carbon atoms, alkanoylamino having 2 to 4 carbon atoms, benzamido, alkylsulfonamido containing l to 4 carbon atoms and phenylsulfonamido, the substituent - (CH _{2) n} Y ² wherein n is 0-4 and Y ² is selected from the group consisting of carboxy, carbamoyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N-alkylcarbamoyl in which the alkyl radical contains 1 to 4 carbon atoms, Ν, Ν-dialkylcarbamoyl in which each alkyl radical contains from 1 to 4 carbon atoms, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 1-oxothiomorpholinocarbonyl, 1,1-dioxothiomorpholinocarbonyl, alkylsulfonamidocarbonyl contains 1 to 4, carbon atoms, phenylsulfonamidocarbon and benzenesulfonamidocarbonyl, -X ³ -L ² -Y ² , wherein X ³ is CON (R ⁵ ), CON (R ² -Y ² ), C (R ⁵ ) 2 O, O, N (R ³ ); ⁵ ) or N (L ² -Y ² ), L ² represents an alkylene group having 1 to 4 carbon atoms, Y * has the meanings given above and each R ⁵ independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and a substituent -X ³ -L ³ Y ', wherein X ³ is CON (R ⁵ ), CON (R ¹ -Y ¹ ), C (R ⁵ ) 2 O, O, N (R ⁵ ) or Ν (ΐΛΥ'), L ³ represents an alkylene group having 2 to 4 carbon atoms, Y ¹ has the meanings given above and each R ⁵ independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or a substituent selected from the group consisting of piperazin-1-ylcarbonylalkyl in which an alkyl radical having 1 to 4 carbon atoms, and a 4-alkylpiperazin-1-ylcarbonylalkyl group in which each alkyl radical contains 1 to 4 carbon atoms each heterocyclic group in the substituent of group B optionally having 1 or 2 substituents selected from the group consisting of carboxy, carbamoyl, alkyl of 1 to 4 carbon atoms, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, N an alkylcarbamoyl group in which the alkyl radical contains 1 to 4 carbon atoms and a Ν, Ν-dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, and each phenyl group in the substituent of group B optionally bears 1 or 2 substituents selected halogen, trifluoromethyl, cyano, (C 1 -C 4) alkyl, (C 2 -C 4) alkenyl, (C 4 -C 4) alkynyl, (C 1 -C 4) alkoxy, (C 2 -C 4) alkenyloxy up to 4 carbon atoms and alkynyloxy of 2 to 4 carbon atoms; X ¹ has the meanings specified in claim 1; R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxy, oxo, carboxy and alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms and one of the following groups: - (CH ₂₎ ^-R in which n represents 0 and R ^a is an alkyl radical containing 1 to 4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, carboxyalkyl in which the alkyl portion contains 1 to 4 carbon atoms or an alkoxycarbonylalkyl group in which the alkoxy radical and the alkyl radical contain 1 to 4 carbon atoms; - (CH ₂ ) _n -CO-NRR ¹ in which n 'is 0, 1 or 2 and R and R ¹ are hydrogen or C 1 -C 4 alkyl or R and R ¹ together form a 1-pyrrolidinyl group 1-piperidino, 1-piperazinyl or 4-morpholino; and X and Q are as defined in claim 1; and pharmaceutically acceptable salts thereof.